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A recent study published in Scientific Reports suggests that white blood cells in people with major depressive disorder show altered activity in genes typically associated with brain connections. This provides evidence that the biological footprints of depression extend well beyond the brain and into the immune system, offering a whole-body perspective on the condition.
The research was conducted by a team at the University of São Paulo in Brazil, with support from the São Paulo Research Foundation. The team included Otávio Cabral-Marques, a professor at the University of São Paulo Medical School and coordinator of the research, along with Anny Silva Adri, who conducted the study as part of her doctoral research. They focused on how genetic instructions overlap across completely different types of human tissue.
“We mapped this network of genes that drives the interaction between the immune and nervous systems,” Cabral-Marques says. “Depression is a systemic phenomenon, meaning it spreads throughout the entire body. And the immune system is one of the systems that decentralizes this condition, spreading it beyond the central nervous system. For that reason, it’s not uncommon for a person with depression to exhibit other symptoms, such as skin inflammation or loss of appetite, for example.”
Major depressive disorder is a complex psychiatric condition characterized by persistent low mood, a loss of interest in daily activities, and various physical symptoms. Because the symptoms vary so widely from person to person, understanding the biology of the disorder requires looking at many different systems in the body. Scientists increasingly focus on the relationship between the central nervous system and the immune system.
The research group has spent years exploring this exact overlap between neurological and immune functions. “What we’ve seen in these studies is that there’s a very strong connection between the immune and neurological systems created by this network of genes we’re investigating,” Cabral-Marques says. “Everything is closely linked, and the division between those systems is merely for educational purposes.”
In the human body, peripheral leukocytes act as the primary white blood cells responsible for protecting against illness and disease. These immune cells do not simply float passively in the bloodstream awaiting an infection. They contain many of the same biological components found in the brain, including receptors and enzymes that process neurotransmitters.
Neurotransmitters are the chemical messengers that allow nerve cells to communicate across small gaps known as synapses. While scientists usually study these molecules in the context of brain signaling, evidence suggests they also help direct how white blood cells behave during an immune response. People with depression often show distinct changes in how their white blood cells process these chemical signals.
Every person has a unique genome containing their entire genetic sequence. What distinguishes a neuron from a white blood cell is genetic activation, which dictates which specific genes are turned on or off. This activation depends on the specific function, condition, or environment of the individual cell.
To examine these shared genetic patterns, the authors designed an observational systems biology study combining multiple existing databases of genetic information. They analyzed data from more than 3,000 blood samples stored in public banks across the United States, Germany, and France. They gathered transcriptomic data, which shows exactly how often specific genes are turned on or off, from previous high-throughput sequencing studies.
High-throughput sequencing is a laboratory technology that allows scientists to rapidly read millions of genetic sequences. The final analysis included 1,864 individuals diagnosed with major depressive disorder and 1,208 healthy individuals serving as a comparison group. The scientists compared the genetic activity in the white blood cells of the depressed patients to that of the healthy individuals.
The researchers identified 1,383 altered genes in the defense cells of patients with major depressive disorder. Of those, 73 genes are traditionally associated with synapses, including neurotransmitter transmission and the formation of neural connections. In white blood cells, these same genes participate in immune and inflammatory pathways throughout the body.
The researchers then applied a mathematical technique called linear discriminant analysis to see if these genetic changes could reliably separate the depressed patients from the healthy ones. This method reduces complex data to find the most distinct patterns separating different categories of people. They found 18 specific synapse-related genes that consistently distinguished individuals with depression from those without the disorder.
“It’s a data science study that still needs to be biologically confirmed, but it opens up interesting possibilities for the future development of a panel to identify genes present in immune system cells circulating in the blood that are involved in depression,” Adri says. “Since blood is more accessible than brain tissue, the identified genes serve as biological markers of the presence and severity of depression.”
The scientists also examined genetic data from seven different brain regions known to be involved in mood regulation. They cross-referenced the altered immune genes with genetic data from areas like the anterior cingulate cortex and the orbitofrontal cortex. Through this comparison, they discovered seven specific synapse-related genes that were altered in both the immune cells and the brain regions.
To understand the broader health implications of these seven shared genes, the authors mapped them against a database of known human diseases. This network analysis revealed that these specific genes are also linked to bipolar disorder, psychoses, anxiety, hypertension, arterial diseases, and psoriasis. The mapping also identified connections with gastrointestinal symptoms, erectile dysfunction, and complications related to coronavirus.
“The analysis suggests that these same genes are involved in vascular and inflammatory comorbidities that are common to depression,” Adri says. “Depression isn’t confined to the brain but affects the body in an integrated and molecular way.”
This molecular overlap provides evidence that the genetic disruptions seen in depression might contribute to the physical health problems that often accompany the psychiatric disorder. “Inflammation and molecular dysregulation affect not only the brain but also different organs and systems, amplifying the impact of the disease and suggesting new approaches for diagnosis and treatment,” Adri says.
While the findings offer a detailed look at the overlap between the immune system and the brain, the authors caution against overstating the biological meaning of these genetic patterns. Finding synapse-related genes in white blood cells does not mean that immune cells form actual, functioning synapses like neurons do. The study relies entirely on existing data, meaning it is an exploratory analysis rather than a direct biological experiment.
Because the researchers looked at data gathered at a single point in time, they cannot determine whether the altered gene activity causes depression or if depression causes the altered gene activity. Future research will need to track patients over time to see how these genetic profiles change as depression symptoms worsen or improve. Scientists also need to conduct physical experiments in the laboratory to see exactly what these synapse-related genes are doing inside living white blood cells.
The authors note that the link between peripheral inflammation in the blood and central symptoms in the brain paves the way for future treatments that target inflammation to alleviate depressive symptoms. By combining different types of biological data, researchers hope to eventually confirm the precise role these shared genes play in the human body.
The study, “Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients,” was authored by Anny Silva Adri, Adriel Leal Nóbile, Débora Gomes de Albuquerque, Pedro Marçal Barcelos, Fernando Yuri Nery do Vale, Roseane Galdioli Nava, Yohan Lucas G. Correa, Lena Friederick Schimke, Luiz Fernando Onuchic, Rodrigo Dalmolin, Rafael Machado Rezende, Haroldo Dutra Dias, Igor Salerno Filgueiras, and Otavio Cabral-Marques.